The functional exchange of nutrients and wastes between blood and tissue occurs in the micro-vascular vessels, extending from the arterioles through the capillaries and into the venules. Cortical micro-vascular networks can be described by topological characteristics, such as: vascular density, orientation of the micro-vessels in coherent pathways, branching, and tortuosity. Tortuosity is coiling and looping of micro-vessels upon shrinking of the cerebral tissue and occurs during healthy aging and in pathological conditions. This change in micro-vascular topology has important implications on the delivery of nutrients and removal of wastes from neurons and glial cells in the cortex. The main objective of the proposed USA-France collaborative effort is to develop a computational imaging approach to quantify the microstructure of cerebral vasculature and predict its evolution in aging subjects. Objectives and Methods: The research team has developed several MRI methods that target different characteristics of micro-vascular flow in the brain, including using diffusion-weighted imaging schemes with the intravoxel incoherent motion (IVIM) technique and the use of localized magnetic tagging of blood with the Flow ENhancement of Signal Intensity (FENSI) method. These techniques provide diverse information and tunable sensitivity to investigate micro-vascular flow. Combined with a computer simulation of vascular trees, the structural characteristics of the microvasculature can be extracted using these measures. An animal model of aging will be investigated with histology to determine vascular topology in different regions of the brain and to determine age-related topological changes, especially increasing tortuosity. This information will be used to perform a large-scale simulation of micro-vascular flow to characterize the relationship between micro-vascular topological features and MRI signals. An animal MRI experiment will be conducted with subsequent histological examination to confirm the vascular topological characterization provided non-invasively by MRI. The animal age-related topological features will then be used to predict human age-related vascular changes and a large-scale simulation of human vascular networks and MRI acquisitions will be performed. MRI acquisitions on young and old adult subjects will characterize subject-specific vascular topology and anatomically-specific vascular changes in human cortex, non-invasively. Intellectual Merit: Prior studies of the topology of particular brain regions have been performed via invasive methods on post-mortem tissues and result in discussions of average brain changes across age, not specific to a particular individual. The proposed MRI methods will allow the non-invasive probing of the micro-vascular topology in the human gray matter. This is possible owing to (a) the high spatial resolution afforded by the MRI sequences which can resolve the cortical layer on the spatial scale of vascular organization, and (b) the numerical simulation of the MRI signal on complex micro-vascular networks. The in vivo characterization of micro-vascular topology will provide quantitative descriptions of regional variations in the cortex, which could form the basis of an atlas of micro-vascular topology. In addition it will provide quantitative measures of the disruption of the topology with age in a subject specific and region-specific manner. Broader Impacts: Aging is associated with reductions in cerebral blood flow, reductions in vascular reactivity to compensate for challenges or stimulation, and modifications to the microstructure of capillaries in the brain. Associated with these changes are reductions in cognitive performance. As the population in the US and Europe ages, it is critical to determine how the aging population can maintain long, productive, and independent lives. Our approach will enable non-invasive assessments of microstructural changes in the vasculature to determine causative effects on age-related changes or impacts of cardiovascular interventions, such as aerobic exercise. Computation-enabled imaging of the micro-vascular topology will usher in a continuum of research examining the variation of the metabolic support of brain neurons and glial cells in aging or disease. Integration of Research and Education: Knowledge gained from this project will be disseminated as computer simulations and data relating to micro-vascular flow through the Physiome organization and through web sites associated with other human physiology simulation codes being developed by the research team. This information will be integrated into undergraduate and graduate course offerings by the research team, including: Modeling Human Physiology, Modeling Human Physiology Lab, Cellular Bioenergetics, and other fluid mechanics and mass transport courses.